There are a number of symptoms associated with hypogonadism, categorised as sexual, psychological and physical symptoms. Two retrospective analyses of men who presented to the same outpatient men’s health clinic with a complaint of low testosterone (T) are summarised below. Both studies involved retrospective analysis of the charts of consecutive, T supplementation (TS) naïve men; aged 40–90 years (n=360),1 and those aged <40 years (n=352).2 All men had their T levels measured and completed the Androgen Deficiency in the Aging Male (ADAM) questionnaire which assessed 10 hypogonadal symptoms.

Key Points

A retrospective analysis from a single US centre (between May 2013 and March 2014) involving TS naïve men presenting with symptoms of low T, aged 40–90 years (n=360; mean age 57.1±11.4 years; mean total T level 337.8±147.2 ng/dL) and <40 years (n=352; mean age 33.2±4.2 years; mean total T level 308±170 ng/dL)

In men aged 40–90 years, decreased libido, lack of energy, decrease in strength or endurance, falling asleep after dinner, and deterioration in the ability to play sports all exhibited significant differences (p<0.05) between men with serum T levels <300 ng/dL and >300 ng/dL

In men aged <40 years, the occurrence of feeling sad, lack of energy, decreased strength and endurance, deterioration in work performance, and a deterioration in the ability to play sports were significantly different (p<0.05) between men with serum T levels of <400 ng/dL and >400 ng/dL

Rather than a single predefined total serum T, different thresholds of T levels based on symptomatology are recommended

What is known

Historically a total serum T threshold of 300 ng/dL defined hypogonadism.3 Indeed, it has been shown that in most men T >300 ng/dL predicts a low likelihood of clinically significant hypogonadism.2 However, it should be noted that this threshold was based on a panel consensus.4 Symptoms can vary greatly between men with low T levels, such that a single serum threshold is not appropriate.5,6 Despite the suggested threshold, the T level below which symptoms are most apparent and would benefit TS is largely unknown and varies with age, the presence of comorbid conditions and affected target organs.2

Previously, it has been shown that there is a close association between low energy and testosterone levels.7-9 In a study of hypogonadal and eugonadal men, hypogonadal men reported greater fatigue (10.0 vs 7.0 on a question scale, p=0.03).9 In addition, in a placebo controlled study, hypogonadal men treated with T reported significantly less fatigue (p=0.03 vs placebo control).8 Furthermore, sexual symptoms, notably libido and erectile function, have been thought of as the best predictor of low T levels, as erectile dysfunction is common in hypogonadal men.10

What this study adds

Despite a T level of ≤300 ng/dL being recommended for treating hypogonadism,3 and previous findings suggesting low likelihood of hypogonadism in men with T levels >300 ng/dL, the studies reported here found a number of patients presenting symptoms with T levels between 300–400 ng/dL.1,2 Indeed, it was suggested that in men aged 40–90 years there are multiple symptom-specific thresholds, and in men aged <40 years physical and psychological symptoms were most closely associated with a T level of <400 ng/dL.2

Contrary to previous studies,10-12 in men aged 40–90 years there were no symptoms from the ADAM questionnaire that were significantly predictive of T levels <300 ng/dL. Furthermore, in men aged <40 years only a lack of energy was predictive of T levels <400 ng/dL.

In contrast with previous findings, none of the sexual symptoms predicted a low T level. Men aged 40–90 years only displayed a significant difference in the prevalence of reduced libido, however in the univariate and multivariate analyses, for both men aged <40 years and 40–90 years, there were no sexual symptoms predictive of low T. In men aged 40–90 years, erectile dysfunction was the most often reported symptom, but contrary to results from the European Aging Male study10 it did not predict a T level <300 ng/dL.

One of the main differences noted between young and middle-aged and elderly men, was the prevalence and clustering of different symptoms between the age groups, especially noted in the sexual specific category, suggesting that specific age and population-based questions should be taken into consideration before initiating TS.

Rather than a single pre-specified testosterone level, a range of 320–375 ng/dL based on different symptoms is more appropriate in men aged 40–90 years.1 Furthermore, in men aged <40 years a total serum T level of 400 ng/dL was identified as there were no symptoms that predicted T levels <300 ng/dL.2

These findings confirm that serum testosterone is the laboratory measure most important for confirming a clinical suspicion of hypogonadism.13 Furthermore, although reference ranges (for partitioning testosterone levels into low or normal) are essential for the diagnosis of androgen deficiency,14 it is clear that symptoms accumulate gradually with decreasing testosterone levels.15

Figures

Figure 1. Prevalence of hypogonadal symptoms in men with T levels <300 ng/dL and >300 ng/dL in men aged 40–90 years (p<0.05 for all symptoms)

Figure 2. Prevalence of hypogonadal symptoms in men with T levels <400 ng/dL and >400 ng/dL in men aged <40 years (p<0.05 for all symptoms)